AB0104 THE CAUSAL EFFECT OF LIPID METABOLISM ON THE RISK OF PSORIATIC ARTHRITIS: A MENDELIAN RANDOMIZATION STUDY
Authors: Y. Jin, J. Zhu, H. So, P. Wong, L. S. Tam, D. Wu
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Psoriatic disease, including psoriatic arthritis (PsA) and psoriasis, is driven by a combination of genetic, biomechanical, metabolic, and microbial factors which promote an aberrant immune response and the consequent development of chronic disease.(1) Genetic evidence has indicated that body mass index and glycemic control are associated with an increased risk of psoriasis and PsA, and also with an increased risk of cardiovascular disease.(2) However, the causal relationship between serum lipids and risk of incident PsA remains unclear. <h3>Objectives</h3> To investigate whether lipid metabolites are causally associated with incident psoriatic arthritis (PsA), in comparison with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). <h3>Methods</h3> The publicly available summary-level findings from two genome-wide association studies (GWAS) were used to identify loci influencing circulating metabolites as exposure and a GWAS for PsA (n=1,637, control=212,242), RA (n=6,236, control=147,221), AS (n=1,462, control=164,682) as the outcome. Bi-directional Mendelian randomization (MR) analysis and multivariable MR analysis were used in main and validation analysis. <h3>Results</h3> In the main analysis, pooled data suggested a causal association of PsA risk with total cholesterol (P=0.005), cholesterol esters (P=0.003), free cholesterol (P=0.009), total lipids (P=0.004), phospholipids (P=0.010), and concentration of particles (P=0.005) in large low-density lipoprotein (LDL); total cholesterol (P=0.009), cholesterol esters (P=0.006), total lipids (P=0.009), phospholipids (P=0.002), and concentration of particles (P=0.009) in medium LDL; total cholesterol (P=0.001), total lipids (P=0.001), concentration of particles (P&lt;0.001) in small LDL (Figure 1). Multivariable MR analysis identified cholesterol esters in large LDL as the strongest causal risk factor for PsA (P=0.017) (Table 1). In validation analysis, genetically predicted cholesterol (P=0.004), cholesteryl esters (P=0.001), and total lipids (P=0.003) in LDL; cholesteryl esters in large LDL (P=0.006); phospholipids (P=0.007) and concentration of particles (P=0.006) in medium LDL; and total lipids in small LDL (P=0.008) were also causally associated with PsA. However, there is no causal association of lipid metabolites with RA and AS. <h3>Conclusion</h3> The present findings supported causal relationships between LDLs and an increased risk of PsA, especially for cholesterol esters in large LDL. <h3>References</h3> [1]Schett G, Rahman P, Ritchlin C, McInnes IB, Elewaut D, Scher JU. Psoriatic arthritis from a mechanistic perspective. Nat Rev Rheumatol. 2022;18(6):311-25. [2]Zhao SS, Bellou E, Verstappen SMM, Cook MJ, Sergeant JC, Warren RB, Barton A, Bowes J. Association between psoriatic disease and lifestyle factors and comorbidities: cross-sectional analysis and Mendelian randomisation. Rheumatology (Oxford). 2022 Jul 21:keac403. <h3>Acknowledgements</h3> We are immensely grateful to the study participants from the circulating metabolites GWAS study. <h3>Disclosure of Interests</h3> None Declared.